5-nitroimidazoles



United States Patent Office 3,483,212 Patented Dec. 9, 1969 US. Cl. 260-309 10 Claims ABSTRACT OF THE DISCLOSURE A novel class of S-nitroimidazole derivatives bearing electron withdrawing l-side chains effective in the treatment and prevention of trichomonal infections is disclosed and a suitable means of preparing such compounds is described.

Background of the invention This invention relates to novel and useful imidazole derivatives and, more particularly, to certain S-nitroimidazole compounds possessing electron withdrawing groups in the 1-position which are effective anti-trichomonal agents. Examples of trichom nal infections include trichomonal vaginitis, a troublesome vaginal infection caused by the parasitic protozan Trichomonas vaginalis and bovine trichomoniasis caused by Trichomonas foetus. Up to now, various medicaments and methods of treatment have been used with varying degrees of effectiveness. Moreover, in the treatment of vaginitis a number of different drug classes are involved, for example, sulfonamides, fungicides, penicillin, vaginal cleansers, etc. In addition, product forms such as ointments, jellies, creams, powders, oral tablets and others have been used.

Summary of the invention Accordingly, the present invention discloses compounds having the formula:

N N no.

wherein n is an integer from 1 to 3; R' is alkyl having from 1 to 4 carbon atoms; Y is selected from the group consisting of SF SO CF -SO NH SO NHR, SO NR NHCF N(CF CH(SO R) CH(COOR) )2, z)2 2)3 and NO wherein said R groups contain from 1 to 4 carbon atoms and the pharmaceutically-acceptable acid addition salts thereof.

A particularly preferred emb diment of the herein described invention concerns those compounds represented by the above formula when R is methyl and n is 2.

Detailed description of the invention The novel derivatives disclosed herein are prepared by the synthetic scheme outlined herein below:

wherein R, n and Y are as defined earlier. The symbol p-ts signifies the p-toluenesulfonyl radical having the chemical structure:

The above reaction is generally carried out without a solvent although it is possible to utilize a solvent provided its boiling point is sufiiciently high at allow temperatures at reflux which are adequate for complete reaction. This particular temperature range is from about 150 C. In most instances, however, no solvent will be used and the mixture of p-toluenesulfonate and 5-nitroimidazo1e is simply heated to a temperature of from to about C. with stirring and held there for a period of from about 3 to about 5 hours. The resulting mixture is extracted with warm water subsequently made basic (pH 9) with a 10% sodium carbonate solution. The reaction product as free base is then extracted with an organic solvent, for example, chloroform separated, dried and isolated by evaporation of solvent. The oil residue crystallizes on standing and may be recrystallized.

The S-nitroi-midazole starting materials are either commercially available or described in the literature and can be easily made by well-known organic synthetic procedures. As for the p-toluenesulfonate starting materials, a suitable working procedure has been worked out and can be shown chemically by the following sequence:

To p-toluenesulfonyl chloride dissolved in ethylene dichloride is added the appropriate alcohol followed by the addition of a slight molar excess of a 40% aqueous solution of sodium hydroxide. During the addition of base, the reaction temperature is maintained at 1525 C. by means of an ice-bath. On completion of addition, the reaction mixture is stirred at room temperature for another 10-20 hours and then diluted with water. The ethylene dichloride layer is separated, Washed with 2 N HCl and then water, and then dried sodium sulfate. The dried solution is then concentrated leaving an oil residue product. Generally, this resulting intermediate can be used directly in the next step in the condition it is isolated; however, if desired, it can be crystallized from a suitable solvent or allowed to crystallize on standing.

The S-nitroirnidazole compounds disclosed herein are preferably administered as such or in the form of acid addition salts containing pharmaceutically-acceptab1e anions. Examples of acids which provide pharmaceutically-acceptable anions are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, or sulfurous, phosphoric, acetic, lactic, citric, tartaric, oxalic, succinic, maleic and gluconic. The conversion of the herein disclosed S-nitroirnidazole compounds to their acid addition salts comprises treating said compounds with a substantially equimolar amount of a chosen acid in a suitable organic solvent such as methanol or ethanol. Since the acid addition salts of the novel compounds disclosed herein are somewhat unstable under aqueous conditions, especially in aqueous acid solutions, it is preferred to prepare such salts under anhydrous conditions. When such salts are to be used for human consumption, either orally or parenterally, the acids which are used to prepare the pharmaceuticallyacceptable addition salts must, of course, be those which necessarily form non-toxic acid addition salts.

The method of treatment employed for the control of trichomonal infections which is particularly preferred is oral administration, however, topical and parenteral application are also found to be suitable. Moreover, said oral medicament can be supplied in the form of a tablet formulation characterized by high trichomonadicidal power and capable of giving symptomatic relief to the host.

The activity of the novel herein disclosed compounds is determined by an in vivo test in the following manner: animals to be tested are inoculated with a trichomonal test organism (intra-peritoneally). Dose levels of antitrichomonal agent ranging from to 200 mg./kg. is administered orally over a period of three days once a day. On the completion of said time period, a comparison is made based on the number cleared of infection/ number of infected animals, between those treated with the herein disclosed anti-trichomonal agents and a control, I-(Z-hydroxyethyl)-2-methyl-S-nitroimidazole.

The following examples are provided by way of illustration and should not be interpreted as limiting the in vention, many variations of which are possible without departing from the spirit or scope thereof.

EXAMPLE I 1- 2-nitroethyl) 2-methyl-5-nitroimidazole (A) A mixture containing Z-methyl-S-nitroimidazole (12.7 g.) and 2-nitroethyl-p-toluenesulfonate (45 g.) is stirred and heated to 140 C. for about 3-4 hours. After this heating period, the reaction mixture is allowed to cool and then extracted with hot water (3X with 200 ml.). The aqueous phase is then adjusted to a pH of 9 with 10% sodium carbonate solution and then extracted three times with 150 ml. portions of chloroform. The chloroform extract is separated, Washed, dried and evaporated almost to dryness. On standing, the product crystallizes.

(B) The necessary reagent 2-nitroethyl-p-toluenesulfonate used above is prepared in the following manner:

To a solution of p-toluenesulfonyl chloride (95 g.) in ethylene dichloride (125 ml.) is added 2-nitroethanol (49 g.) followed by the addition of 22 g. of a 40% aqueous sodium hydroxide solution. This latter addition is over a /2 hour period and the temperature of the reaction mixture is held at l525 C. during this time by means of an ice-bath. On completion, the mixture is stirred for another 20 hours at room temperature. The organic phase is separated, washed with 2 N HCl, then water, dried and evaporated to dryness to give a good yield of product.

EXAMPLE II 1- (2-trifluoromethylsulfonylethyl) -2-methyl-5 nitroimidazole The procedure of Example I (part A) is repeated wherein a stoichiometric equivalent amount of Z-trifluoroi methylsulfonylethyl-p-toluenesulfonate is used in place of 2-nitroethyl-p-toluenesulfonate with comparable results.

Similarly, 2 tritluoromethylsulfonylethyl-p-toluenesulfonate is prepared by means of the procedure outlined in part B of Example I wherein a stoichiometric equivalent amount of 2-trifiuoromethylsu1fonyl ethanol is used in lieu of Z-nitroethanol with good results.

EXAMPLE III 1- Z-aminosulfonylethyl) -2methyl-S-nitroimidazole The procedure of Example I (part A) is repeated wherein a stoichiometric equivalent amount of Z-aminosulfonylethyl-p-toluenesulfonate is used in place of 2- nitroethyl-p-toluenesulfonate with comparable results.

Similarly, Z-aminosulfonylethyl-p-toluenesulfonate is prepared by means of the procedure outlined in part B of Example I wherein a stoichiometric equivalent amount of Z-aminosulfonylethanol is used in lieu of 2-nitroethanol with good results. i

EXAMPLE IV 1-(2-pentafiuorothioethyl) -2-methyl-5 -nitroimidazole The procedure of Example I (part A) is repeated wherein a stoichiometric equivalent amount of Z-pentafiuorothioethyl-p-toluenesulfonate is used in place of 2- nitroethyl-p-toluenesulfonate with comparable results.

Similarly, 2-pentafluorothioethyl-p-toluenesulfonate is prepared by means of the procedure outlined in part B of Example I wherein a stoichiometric equivalent amount of Z-pentafluorothioethanol is used in lieu of 2-nitroethanol with good results.

EXAMPLE V 1- Z-ditrifluoromethylaminoethyl) -2-methyl-5- nitroimidazole The procedure of Example I (part A) is repeated wherein a stoichiometric equivalent amount of 2-ditrifluoromethylaminoethyl-p-toluenesulfonate is used in place of 2-nitroethyl-p-toluenesulfonate with comparable results.

Similarly, 2 ditrifluoromethylaminoethyl-p-toluenesulfonate is prepared by means of the procedure outline in part B of Example I wherein a stoichiometric equivalent amount of 2-ditrifluoromethylarninoethanol is used in lieu of 2-nitroethanol with good results.

EXAMPLE VI 1- 2-trifiuor0methylaminoethyl) -2-methyl-5- nitroimidazole The procedure of Example I (part A) is repeated wherein a stoichiometric equivalent amount of 2-trifluoromethylamino ethyl-p-toluenesulfonate is used in place of 2-nitroethyl-p-toluenesulfonate with comparable results.

Similarly, 2 trifluoromethylaminoethyl-p-toluenesulfomate is prepared by means of the procedure outline in part B of Example I wherein a stoichiometric equivalent amount of Z-trifluoromethylaminoethanol is used in lieu of Z-nitroethanol with good results.

EXAMPLE VII 1- Z-dimethylsulfonylmethylethyl) -2 -methy1-5 nitroimidazole 6 EXAMPLE VIII ing Of SF $0 01 SO NH -SO NHR, AO NR I-(Z-dicyanomethylethyl)-2-methyl-5-nitroimidazole 3: 3)2 2 02, CH(COOR) The procedure of Example I (part A) is repeated wherein a stoichiometric equivalent amount of 2-dicyanomethylethyl-p-toluenesulfonate is used in place of 2-nitroethyl-ptoluenesulfonate with comparable results.

Similarly, 2-dicyanomethylethyl-p-toluenesulfonate is prepared by means of the procedure outlined in part B of Example I wherein a stoichiometric equivalent amount of 2-dicyanomethylethanol is used in lieu of Z-nitroethanol g ig f fa s 4 g ggg ggi with good resultsand the pharmaceutically-acceptable acid addition salts EXAMPLE IX thereof. The procedure of Example I (part A) is repeated where- 2. A compound as claimed in claim 1 wherein R is in stoichiometric. amounts of the following S-nitroimid- CH andn is 2. azole derivatives and p-toluenesulfonates are reacted in 3. A compound as claimed in claim 2 wherein Y is place of Z-methyl-S-nit'roimidazole and 2-nitroethyl-p- -SO CF toluenesulfonate, respectively, with the indicated products 4. A compound as claimed in claim 2 wherein Y is being obtained in substantial yields: SO NH 5-nitroimidazole derivative p-Toluenesulfonate Product 2-ethy1-5-nitr0imidazole 1-(methylaminosulfonyl)methy1p-t0luenesulfonate. 1-l-nethylaminosulfonyl-methyl))-2-ethy1-5-nitro- 1 am e.

2-propyl-5-nitroimidaz0le B-(butylaminosulfonyl) propyl-p-toluenesultonate 1-(3-1;gtylaminosulfonyl-propyl)-2-propy1-5-nitro- Z-butyl-Sdlitroimidazole 1-(diethylaminosulfonyl)methyl-p-toluenesulfonate. 1-t1-dethylaminosulionylmethyl)-2-butyl-5-nitrolml 8Z0 6.

2-isopropyl-5-nitrolmidazole 2-(dibutylsulfonylmethyl)ethyl-p-toluenesulfonate 1-[2-(dibutylsulfonylmethyl)]ethy1-2-isopropy1-5- nitroimidazole.

2-isobutyl-5-nitroirnidazole 1-(diethylsulfonylmethybmethyl-p-toluenesulfonate. 1-(l-diethylsulfonylmethyl methy1)-2-isobuty1-5- nitroimidazole.

2 methy1-5-nitroimidazole 2-(dibutylsuh'onylmethyl)-ethyl-p-toluenesulfonate. 1-(2-dbutylsultonylmethyl ethyl)-2-methy1-5-nitro- 2-ethyl-5-nitroimidazole B-(dicarbomethoxymethyl)-propyl-p-toluenesulfo-. 1-(3-dicarbomethoxy-methylpro yl)-2-ethy1-5- nate, nitroimidazole.

zm yl-s-nitroimidazole 4-(diearbobutoxymethyl)-butyl-p-t01uenesu1fonate 1-(4-(1icarbobutoxy-methylbutyl)-2- ro y1-5- nitroimidazole.

2-isopropyl-5-nitroimidazole 2-trifluoroacetylethyl-p-toluenesulfonate 1-(Z-trifiuoroacetylethyl)-2-isopropyl-5-nitroimidazole,

2butyl-5-nitroimidazole 3-(tricyanomethyl)propyl-p-toluenesulfonate 1-(3-tricyan0methyl-pr0py1)-2-but;y1-5-nitr0imidazcle.

2-methyl-5nitroimidazole 4-(dinitromethy1)butyl-p-tolueuesulfonate 1-(4-dinitromethy1butyl)-2-methy1-5-nitroimidazole.

Z-ethyl-Smitroimidazole 1-(trinitromethyl)methyl-p-toluenesultonate l-(trinitromethyl methyl)-2-etl1yl-5-nitroimidazole EXAMPLE X 5. A compound as claimed in claim 2 wherein Y is The S-nitroimidazole compounds disclosed herein may be converted to their acid addition salts by the following (8;? as damned m clalm 2 Wherem Y 1S general procedure:

To a methanolic solution containing the S-nitroimidazole A compound as damned In Claim 2 Wherem Y 15 -NH--CF free base (1 mole) is added a stolchiometric equivalent 3 amount of a suitable acid. The resulting solution is subse- A compound as clalmed 111 Glam! 2 Wherem Y 15 quently stripped free of solvent and the precipitated prod- 2 s)2- net is filtered and dried. Other solvents, for example, A CQmPOUIId as clalmed n C m 2 Wh rem Y 18 ethanol, may be used. The following acid addition salts CH(CN) I I are typical examples prepared using the above procedure 10. A compound as claimed 1n claim 2 wherein Y 15 and substantial yields of product are obtained: --NO Free Base Acid Acid Addition Salt ..HC1 1-2-'t thl-2- llhl-5-'t id lhd ma. i-g-fiiii ii yiltfii iri igfiiir r igil iiiyi-s- HBr 1-523353311orzilthglsul my lligll -n t iigl-gnigbir lilaiolehydrobromide.

nitroimidazole. 1 Hr 1-2 1r ltl1 l-2 thl-5-t' d lhd'd'd. i-E3.ifitalifilliltiiiilfin fiililiilfiiiililiili em 6661-." 1-Eeiillihfihfifiiriafin-5?neuly1- l$$63$6 itftfi.

What is claimed is: References Cited 1. A compound Of the formula: 65 3,244,726 4/1966 Karmas 260309 3,376,311 4/1968 Butler 260309 N 3,399,193 8/1968 Giraldi et a1. 260309 IL FOREIGN PATENTS f 7 1,003,091 9/1965 Great Britain. (CHfln-Y HENRY R. JILES, Primary Examiner NATALIE TROUSOF, Assistant Examiner wherein n is an integer from 1 to 3; R is alkyl of from US. Cl. X.R.

1 to 4 carbon atoms; Y is selected from the group consist- 260456; 424-273 

